The present invention relates to viral vectors and bacterial vectors comprising Crimean-Congo Haemorrhagic Fever Virus (CCHFV) antigens and their use in immunogenic and antigenic compositions.
Crimean-Congo Haemorrhagic fever (CCHF) is a viral haemorrhagic fever caused by a virus of the Nairovirus group (CCHFV). CCHF is a zoonosis, and infects a range of domestic and wild animals. It is spread via the bite of an infected tick. CCHF was first described in the Crimea in 1944 among soldiers and agricultural workers, and in 1969 it was recognised that the virus causing the disease was identical to a virus isolated from a child in the Congo in 1956.
CCHF virus is endemic in many countries in Africa, the Middle East, Eastern Europe and Asia, and outbreaks have been recorded in Russia, Turkey, Iran, Kazakhstan, Mauritania, Kosovo, Albania, Pakistan, and southern Africa in recent years. The first clinical case of CCHF in Greece was reported in July 2008. The global distribution of cases corresponds to those areas where the ticks are found.
The virus is spread by the bite of infected Ixodidae ticks, and the most efficient and common vectors appear to be members of the Hyalomma genus, which commonly infest livestock and other animals. Immature ticks acquire the virus by feeding on infected small animals. Once infected, the tick carries the virus for life, and passes it to animals or humans when it bites them. Domestic ruminants such as cattle, sheep and goats carry the virus for around one week after becoming infected. Most birds are thought to be relatively resistant to infection with CCHF virus, however, many bird species carry Hyalomma ticks, and human cases have occurred in those working with ostriches in the past.
Humans may be infected with CCHF by the bite of an infected tick, contamination with tick body contents, or direct contact with the blood, tissues or body fluids of infected humans or animals. The majority of cases occur in those living in tick infested areas with occupational exposure to livestock, including farmers, veterinarians, slaughter-house workers, livestock owners and others working with animals. Cases also occur in healthcare workers or others caring for infected persons without taking adequate infection control precautions.
CCHF outbreaks are generally associated with a change in situation such as war, population and animal movements, or climatic and vegetation changes which produce more ground cover for small mammals which act as hosts for ticks. These conditions can lead to explosions in tick populations, and allow increased tick/human contact.
The incubation period of CCHF appears to vary according to the mode of acquisition of the virus. If a patient has been infected by a tick bite, the incubation period is usually 1-3 days, and up to 9 days. Infection via contact with infected blood or tissues leads to an incubation period of 5-6 days, and the maximum recorded incubation period is 13 days. The illness begins abruptly, with fever, muscle aches, dizziness, neck pain and stiffness, backache, headache, sore eyes and photophobia (sensitivity to light). Nausea, vomiting and sore throat may also occur, with diarrhoea and abdominal pain. Over the next few days the patient may experience mood swings, confusion and aggression, followed by sleepiness, depression and liver enlargement. More severe symptoms may follow, including petechial rash (a rash caused by bleeding into the skin), bruising and generalised bleeding of the gums and orifices. In severe cases patients develop failure of the liver, kidneys and lungs, and become drowsy and comatose after 5 days. Approximately 30% of cases are fatal.
Diagnosis of CCHF requires highly specialised, high biosafety level laboratory facilities. Antibodies may be detected in serum by about day six of illness. The virus may be isolated from blood or tissue specimens in the first five days of illness, and grown in cell culture, and nucleic acid detection methods may also be used to detect the viral genome. Patients with fatal disease do not usually develop a detectable antibody response, and in these individuals, and those in the early stages of infection, diagnosis is by virus detection. General supportive therapy is given, including replacement of blood components, balancing fluids and electrolytes, and maintaining oxygen status and blood pressure. There is evidence that CCHF responds to treatment with the antiviral drug ribavirin, in both oral and intravenous formulations.
A vaccine based on inactivated CCHF virus has been used in Eastern Europe, however this vaccine is not licensed by the EMA or FDA, and there is no literature to demonstrate its efficacy. There is therefore at present no safe and effective, commercially-available vaccine against CCHFV.
There is therefore a need for new vaccine compositions that demonstrate improved immunogenicity when used in the prevention and treatment of CCHFV infections, in particular in human subjects.